Any reference to background art herein is not to be construed as an admission that such art constitutes common general knowledge in Australia or elsewhere.
Acute promyelocytic leukaemia (APL) is a rare disease, accounting for 10-15% of all acute myelogenous leukaemia in adults. APL is characterised by the accumulation of clonal haemopoietic precursors blocked at specific stages of development. APL is classified under the French-American-British (FAB) morphological scheme as subtype M3 of acute myeloid leukaemia (AML). The bone marrow morphology is characterised by greater than 30% blasts and abnormal promyelocytes; multiple Auer bodies, heavy granulation obscuring the basophilic cytoplasm, and strong positive cytochemistry.
The disease involves a balanced translocation involving chromosomes 15 and 17 (t15:17) although exceedingly rare variants of this leukaemia show balanced translocations of chromosomes 11/17 and 5/17. As a result of these translocations APL blasts invariably synthesize aberrant fusion forms of the retinoic receptor type alpha, PML-RARα in the case of t15:17, PLZF-RARα and NPMRARα in the case of t11:17 and t5:17, respectively. In addition, the breakpoint of the t15:17 chromosomal translocation is heterogeneous, leading to at least three molecular types of PML-RARα fusion proteins. The PML/RARα fusion protein is considered to have an important role in APL pathogenesis by causing a maturation block at the promyelocyte stage of myeloid differentiation. These molecular defects allow the classification of APL patients in two categories: all-trans-retinoic acid (ATRA)-sensitive and ATRA-resistant. Patients with the t15:17 and t5:17 translocations are ATRA-sensitive, and those with the t11:17 translocation are resistant. Among other actions, this mutant protein disaggregates PML Oncogenic Domains (PODs), which are spherical nuclear bodies that are attached to the nuclear matrix. This disorganisation of the PODs is also thought to play a crucial role in APL pathogenesis by causing inhibition of apoptosis mechanisms. The t(15;17) translocation may be evidenced with reverse transcriptase-polymerase chain reaction (RTPCR) using specific PML and RARα oligonucleotides. Depending of the RT-PCR technique used, its sensitivity level may vary between 1/104 and 1/106 cells.
The treatment of newly diagnosed APL patients consists of two phases: an induction phase to achieve remission (defined by bone marrow clearance) and then a set of cycles of consolidation and maintenance.
All-trans retinoic acid (ATRA) coupled with the anthrocycline chemotherapy (CT) (Idarubicin; BLOOD, Vol. 120, No. 8) has been considered as the APL standard first line treatment, although recent data from Iland et al (2012) summarising the Australian Leukaemia and Lymphoma Group's (ALLG) study suggests that in first line therapy, ATRA plus CT, coupled with IV arsenic trioxide, may provide a more effective treatment protocol. Arsenic trioxide had already been established as an effective therapy for patients in a third line setting and these recent results from the ALLG study further highlight the value of arsenic trioxide as an effective treatment in APL.
Although arsenic trioxide (As2O3) is a well-known poison, it has been in medical use for a long time. In 1865, arsenic compounds, (often called Fowler's Solution which is a solution containing 1% potassium arsenite (KAsO2)) was already described for the treatment of chronic myelogenous leukaemia. Because of its chronic toxicity, this treatment was replaced by the non specific alkyl sulfonate chemotherapeutic agent, busulfan in the middle of the 20th century. After a large scale clinical screening, therapeutic effects were identified in some human cancers such as leukaemia, oesophageal carcinoma, and lymphoma.
There are now a number of commercially available treatments for APL which employ arsenic trioxide as the active ingredient in the form of a sterile IV infusion and where the treatment occurs by dilution of the concentrated IV 10 mg/10 mL solution of arsenic trioxide into an infusion bag containing sterile saline or glucose and the patient given the drug given by slow infusion.
Sterile IV formulations of arsenic trioxide and their use in treating various types of leukaemia's are disclosed in U.S. Pat. No. 7,879,364 and WO2004/032822. Since arsenic trioxide is only sparingly soluble in water at physiological or acidic pH these documents describe solubilising arsenic trioxide in an aqueous solution at high pH, such as a pH greater than 12. To assist in dissolving all of the arsenic trioxide and attain a clear solution, stirring and heating are recommended. The solution thereby provided is too basic to be useful as a pharmaceutical composition and so this solution is first diluted in water, for example, to a concentration of about 1 mg/mL, pH 12. The arsenic trioxide solution is then adjusted with hydrochloric acid with constant stirring until the pH is 8.0 to 8.5. The inventors in U.S. Pat. No. 7,879,364 state that highly concentrated hydrochloric acid is not suitable as it causes precipitation. The partially neutralized arsenic trioxide solution is then sterilised and packaged.
The sterile IV formulation has a number of drawbacks. Firstly, it must be prepared (usually by hospital compounding laboratories) by aseptic addition of the 1 mg/mL solution into a sterile infusion bag. Secondly, the form of delivery is by slow infusion of the dilute IV bag, hence a patient must spend a number of hours in hospital on a considerable number of occasions during the induction and maintenance treatment phases over period of about 4 to 6 months. This is a considerable drain on the patients, their families, the hospital resources and medical staff's time.
There is therefore a need for an improved formulation to deliver an active arsenic species useful in the treatment of a number of forms of cancer.